Deubiquitylating Enzymes in Hepatocellular Carcinoma

Abstract

Ubiquitination is a reversible and dynamic process, precisely regulated by ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin ligases (E3), and deubiquitinating enzymes (DUBs). Dysregulation of DUBs disrupts the dynamic balance of ubiquitination, contributing to the development of various diseases, particularly cancer. An increasing number of studies have identified dysregulation of DUBs in various tumor types and have explored their regulatory mechanisms in these contexts. Hepatocellular carcinoma (HCC), the most common form of liver cancer, is highly malignant and has limited treatment options, necessitating the exploration of additional therapeutic strategies. Current research has identified dysregulation of DUBs in HCC, but their mechanisms of action remain poorly understood. Given the large number of DUB family members, there is significant potential for further investigation. This review summarizes the DUBs associated with HCC, including their structures, functions, and the mechanisms through which they regulate HCC development. Furthermore, we provide a brief overview of the discussed DUBs, aiming to offer new perspectives for future HCC research.

Keywords: deubiquitylating enzymes; hepatocellular carcinoma.

Figure 1

Structural representations of DUB catalytic domains across six families. Active site cysteine (for OTUs, USPs, UCHs, MJDs, MINDYs) or zinc (for JAMMs) is highlighted. Representative structures are shown for:(A) USP family (USP7, PDB: 1NB8) (B) OTU family (OTUB1, PDB: 2ZFY) (C) UCH family (UCH-L3, PDB: 1UCH) (D) MJD family (Ataxin-3, PDB: 1YZB) (E) MINDY family (MINDY1, PDB: 5JKN) (F) JAMM family (STAMBPL1, PDB: 2ZNR).

Figure 2

The pathways regulated by deubiquitinating enzymes (DUBs) in the progression of hepatocellular carcinoma (HCC). The figure illustrates the pathways by which DUBs regulate glycolysis, lipid metabolism, ferroptosis, PDL1 synthesis, and multiple signaling pathways in HCC. Arrows (→) indicate promotion or activation, while blocked lines (┫) denote inhibition or suppression. Created in https://BioRender.com.